Protein kinases modulate a wide variety of biological processes of cells, especially those that carry signals from the cell membrane to intracellular targets and coordinate complex cellular functions. Many extracellular stimuli that induce cellular responses to occur inside the cells act through affecting protein kinases and the pathways regulated by these kinases. Consequently, one or more cellular responses such as cell proliferation, differentiation, migration, activation of transcription factors, control of protein synthesis, regulation of cell cycle, secretion of hormones and cytokines/chemokines, and glycogen metabolism can be regulated by these extracellular stimuli. Examples of such stimuli include various environmental stress signals (e.g. oxidative stress; heat shock, ultraviolet radiation, bacterial endotoxin, H2O2), inflammatory cytokines (e.g. tumor necrosis factor a (TNF-β) and interleukin-6 (IL-6)), and growth factors (e.g. epidermal growth factor (EGF), and transforming growth factor beta (TGF-β)).
Due to the importance of protein phosphorylation in regulating many aspects of cell life, aberrant protein kinase activity will result in abnormal phosphorylation of key functional proteins and enzymes and therefore is associated with many human diseases, in particular those involved in proliferative and inflammatory responses, such as cancer, rheumatoid arthritis (RA), chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, osteoarthritis, asthma, as well as cardiovascular and neurological disorders. Accordingly, there has been a substantial effort in medicinal chemistry to develop therapeutic agents targeting protein kinases for the treatment of human diseases.
IKKbeta is a key kinase regulating inflammation and stress related pathways and thus has been linked to the development of a variety of human diseases. For example, intra-articular administration of a dominant-negative IKKbeta significantly reduced the severity of the adjuvant-induced arthritis in rats (Tak PP et al, Arthritis Rheum. (2001) 44(8)1897-1907). IKKbeta knockout cells have dramatic defects in expressing TNFα-induced cytokines, chemokines, or adhesion molecules that are involved in inflammatory disease such as RA and COPD. Through conditional or tissue-specific knockout of IKKbeta, this kinase is found to be required for survival and proliferation of peripheral B-cells and for prevention of apoptosis mediated by TNFα (Li Z-W, Omori A S, Labuda T, Karin M, Rickert R C, “IKKβ is required for peripheral B cell survival and proliferation” The J. Immunol., (2003), 170:4630-4637; Maeda S, Chang L, et al. “IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFα” Immunity, (2003), 19:725-737). Moreover, deletion of IKKbeta in myeloid cells also reduced the growth of colitis-associated cancer (Greten F R et al, Cell, (2004), 118:285-296). Furthermore, several groups have demonstrated that IKKbeta kinase inhibitors can induce cell growth inhibition and/or augment TNFα- or TRAIL-induced cell death in different cancer cell lines (Takaomi et al Clinical Cancer Res., (2005), Vol 11:1974-82; Hideshima et al, JBC, (2002) 277:16639-47; Lam et al Clinical Cancer Res., (2005) Vol 11:28-40).
The present invention provides novel pyrimidinyl benzothiophene compounds believed to have clinical use for treatment of cancer and inflammatory diseases through inhibiting IKKbeta.